The emergence of tumors resistant to anticancer agents has been recognized as one of the major obstacles to effective cancer chemotherapy. Recent studies have elucidated various mechanisms in this resistance, such as induction of drug efflux pumps, in particular certain of the ABC transporters. Experiments to predict the sensitivity of tumors to anticancer agents using DNA microarray and SNPs analyses are ongoing. The development of the new anticancer agent ST1571 and the emergence of tumors resistant to ST1571 indicate the urgent need for clinically available reversing agents.

The substantial advances made in recent years in the molecular biology of malignant urological tumors and the associated progressive analysis of these conditions at a molecular level have spurred research aimed at gene-based treatment. In the field of prostate cancer, while there have been many ground-breaking studies particularly in the United States, none has yet led to a revolutionary treatment for recurrent prostate cancer. Gene-based treatment is being applied seriously in clinical settings, especially in the United States, but so far without significant effect. Many researchers worldwide are devoting energy to the development of effective vectors. By adjusting the promoter, which has the function of directing the vector, we have developed organ-specific vectors for the treatment of prostate cancer. In the present study, which targeted prostate cancer with bone metastasis, we developed a suicide-gene therapy using an adenovirus vector with an organ-specific osteocalcin promoter. Clinical trials of this vector have already been conducted at the University of Virginia in the United States and have so far confirmed the safety of the therapy. In the present paper we present the results of this gene-therapy research from the basic to the clinical phase alongside an outline of related research at our institution. Gene therapy for cancer is now being targeted not only against the primary tumor but systemic cancers including distant metastases; systemic administration of adenovirus vectors with organ-specific promoters may become one of the most promising systemic anti-tumor therapies of the next-generation.

Androgen-deprivation therapy is often the first choice of several therapeutic procedures for advanced prostate cancer. However, despite an initial response to androgen-deprivation therapy, the cancer eventually progresses from an androgen-dependent to an androgen-independent phenotype. Molecular mechanism of development to androgen-independence and recurrence during androgen-deprivation therapy remain unclear. The observation that heterogeneity of AR expression in prostate cancer correlates with malignancy suggests that androgen responsiveness plays an important key role in the progression of prostate cancer. Therefore, it is very important to consider the role of AR and mechanisms of relapse when we treat androgen-independent prostate cancer.

Most of chemical carcinogens are metabolized and activated in vivo by phase I enzymes including the microsomal cytochromes P450 (CYP) and epoxide hydroxylases. The carcinogens and their metabolites are detoxified by the phase II enzymes that include various transferases such as glutathion-S-transferases (GST). Some studies have demonstrated the association of the polymorphisms in CYP2E1 genes with the susceptibility to lung cancer. Subsequently, the polymorphisms appear to be important biomarkers that provide information for assessments of exposure and total burden of environmental carcinogens. Therefore, the investigation of the polymorphisms in these genes will provide information not only for the prediction of individual cancer risks but also for the prevention of cancer. In this review, we will summarize the polymorphisms in the CYP2E1 genes and their relationship to the lung cancer susceptibility and prognosis. Gene polymorphisms such as CYP2E1 will contribute to the evidence based prevention (EBP).

The genomic alterations in preneoplastic lesions are summarized in this review. 3p and 9p in the lung, 9p in the bladder, 8p in the prostata, 19q and 1p in oligodendroglioma, and 22q in meningioma were reported to be deleted. Somatic mutation of p53 was found in preneoplastic lesions of the esophagus, stomach, colon, thyroid, and astrocytoma. Adenoma-carcinoma sequence (Apc, ras, p53 gene alterations) in colon, LKB1 gene in Peutz-Jeghers syndrome, Smad4 in juvenile polyposis, hMSH2, hMLH1, PMS1, PMS2 genes in HNPCC, VHL gene in kidney, WT1 in Wilms tumor, RB gene in retinoblastoma, and ret gene in MEN were reportedly altered in preneoplastic lesions involved in hereditary tumors. Cervical dysplasia and papilloma of the head and neck infected by human papilloma virus and liver infected by B-type hepatitis virus are also precancerous. Genomic instability, APC gene alteration, point mutation of K-ras in preneoplastic lesions of stomach and K-ras and p16 alterations in metaplasia of pancreas were also found. Advances in research on genomic alterations in preneoplastic lesions will contribute to prevention and early detection of cancer.

In this study, we performed a global analysis of the differential gene expression of a gastric cancer cell line established from a primary main tumor (SNU-1) and that of other cell lines established from the metastasis to the peritoneal cavity (KATO-III, SNU-5, SNU-719, MKN45P, HS39). The application of a high-density cDNA microarray method made it possible to analyze the expression of approximately 21,168 genes. Our examinations of KATO-III, SNU-5, SNU-719, MKN45P, and HS39 showed that several genes were up-regulated in addition to expression of sequence tags (ESTs). The analysis revealed altered up-regulation of CD44 (cell adhesion), CEA, 14-3-3, Ubiquitin A and several kinds of ESTs in gastric cancer cells from malignant ascites. We then analyzed these gastric cancer cell lines with Northern blots and observed preferential up-regulation of these selected genes in cells prone to peritoneal dissemination. RT-PCR confirmed that several genes selected by DNA microarray were also overexpressed in clinical samples of malignant ascites. It is therefore considered that these genes may be related to the peritoneal dissemination of gastric cancers. The results of this global gene expression analysis of gastric cancer cells with peritoneal dissemination promise to provide new insights into the study of human gastric cancer peritoneal dissemination.

Anti-p53 antibodies are autoantibodies induced by mutation of p53 cancer-suppressor gene, and are considered to be indirect markers for p53 gene mutations and abnormally high p53 gene levels. We evaluated the usefulness of the measurement of anti-p53 antibodies by enzymed-linked immunosorbent assay using serum samples from patients with various disorders and normal subjects. The anti-p53 antibody concentration was high in patients with lung, esophageal, gastric, hepatocellular, colonic, rectal or ovarian cancer and significantly differed between the group with neoplasms and those with non-neoplastic disorders. Particularly high concentrations were observed in patients with malignant tumors. The mean agreement rate between anti-p53 antibodies and conventional tumor markers was only 47.8% despite slight differences among disorders. The positive rate increased to 63.0% by their combination assay. In addition, anti-p53 antibodies were independent markers, not complimentary to conventional markers. The mean agreement rate between anti-p53 antibodies and tissue p53 was 70.0%. Though the anti-p53 antibody-positive rate was lower than the tissue p53-positive rate, anti-p53 antibodies may be useful new tumor markers because specimens from the affected tissue are not necessary.

A 63-year-old male was diagnosed as chronic myelomonocytic leukemia with normal karyotype in September 1998. He developed acute myelogenous leukemia (AML-M4Eo) in September 2001. The cytogenetic analysis disclosed double t(3;21) at a ratio of 1/20, and the reverse transcriptase-polymerase chain reaction showed AML1/EVI-1 mRNA. He could not achieve complete remission after two courses of induction chemotherapy, and his leukemia cells carrying double t(3;21) were relatively increased. He died of interstitial pneumonia in December 2001. This is the first leukemia case with double t(3;21) and this chromosomal abnormality might play a role in leukemia cell proliferation by generating two AML1/EVI-1 genes.

We describe the case of a 23-year-old man with acute lymphoblastic leukemia in whom the Philadelphia chromosome was first detected in the late stage of the disease. At diagnosis, the patient's leukocyte count was 39,400/microliter and leukemic cells were positive for CD10, 19, 20, 33, 34 and HLA-DR. Karyotypic analysis at diagnosis revealed 46,XY. Complete remission was achieved after the first induction therapy, but the disease recurred after 9 months. The patient underwent allogeneic peripheral blood stem cell transplantation from his HLA identical mother, but relapse occurred on day 80. The proportion of bone marrow lymphoblasts decreased transiently after donor lymphocyte infusion but later increased, and the patient died on day 362. The Philadelphia chromosome was first detected by karyotypic analysis on day 256. p190-type bcr/abl mRNA transcripts were negative following RT-PCR at the initial diagnosis, but became positive from the first relapse through the late stage. Generally, the product of the bcr/abl fusion gene has been thought to play an important role in leukemogenesis, however the present case suggests that this gene product is also related to disease progression.